US9108924B2 - Process for the preparation of bendamustine hydrochloride - Google Patents

Process for the preparation of bendamustine hydrochloride Download PDF

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Publication number
US9108924B2
US9108924B2 US13/623,536 US201213623536A US9108924B2 US 9108924 B2 US9108924 B2 US 9108924B2 US 201213623536 A US201213623536 A US 201213623536A US 9108924 B2 US9108924 B2 US 9108924B2
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formula
compound
process according
bendamustine hydrochloride
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US20140121383A1 (en
Inventor
Bhuwan Bhaskar MISHRA
Nikunj Shambhubhai KACHHADIA
Vinod Singh TOMAR
Saswata Lahiri
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Fresenius Kabi Oncology Ltd
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Fresenius Kabi Oncology Ltd
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Assigned to FRESENIUS KABI ONCOLOGY LIMITED reassignment FRESENIUS KABI ONCOLOGY LIMITED ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: KACHHADIA, Nikunj Shambhubhai, LAHIRI, SASWATA, MISHRA, Bhuwan Bhaskar, TOMAR, Vinod Singh
Publication of US20140121383A1 publication Critical patent/US20140121383A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/16—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the crucial conversions are reaction of 1-methyl-2-(4′-ethyl butyrate)-5-amino]-1H-benzimidazole 6 with ethylene oxide in the presence of water, sodium acetate and acetic acid, by maintaining at 5° C. for 5 hours and overnight at 20° C. to give 4- ⁇ 5-[bis-(2-hydroxy-ethyl)-amino]-1-methyl-1H-benzimidazol-2-yl ⁇ -butyric acid ethyl ester (dihydroxy ester) 7 as a jelly mass, which on chlorination using thionyl chloride in chloroform and subsequent in situ hydrolysis with concentrated HCl gave bendamustine hydrochloride.
  • the publications also disclose a process for the recrystallization of bendamustine hydrochloride from water and the product obtained is a monohydrate with a melting point of 148-151° C.
  • Ethyl 4-[1-methyl-5-bis-(2-hydroxyethyl)-amino-benzimidazolyl-2]butanoate (4, 4.305 g) was added to chloroform (36 mL) and agitated until a clear solution was formed.
  • the solution was cooled to 0° C.
  • Thionyl chloride (2.175 g) was added to the above solution within 40 minutes, maintaining the temperature of the solution to 0-5° C. by cooling.
  • the reaction mixture was agitated at 0-5° C. for 1 hour.
  • the temperature was raised slowly to room temperature by removing cooling within 2.5 to 3 hrs and subsequently agitated at room temperature for 15 to 16 hrs.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
US13/623,536 2011-09-26 2012-09-20 Process for the preparation of bendamustine hydrochloride Active 2032-11-06 US9108924B2 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US14/576,594 US9643932B2 (en) 2011-09-26 2014-12-19 Process for the preparation of bendamustine hydrochloride

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN2795/DEL/2011 2011-09-26
IN2795DE2011 2011-09-26

Related Child Applications (1)

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US14/576,594 Division US9643932B2 (en) 2011-09-26 2014-12-19 Process for the preparation of bendamustine hydrochloride

Publications (2)

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US20140121383A1 US20140121383A1 (en) 2014-05-01
US9108924B2 true US9108924B2 (en) 2015-08-18

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US13/623,536 Active 2032-11-06 US9108924B2 (en) 2011-09-26 2012-09-20 Process for the preparation of bendamustine hydrochloride
US14/576,594 Active 2032-10-02 US9643932B2 (en) 2011-09-26 2014-12-19 Process for the preparation of bendamustine hydrochloride

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Country Status (5)

Country Link
US (2) US9108924B2 (zh)
EP (1) EP2760842B1 (zh)
CN (1) CN104011029B (zh)
ES (1) ES2613838T3 (zh)
WO (1) WO2013046223A1 (zh)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2720547A4 (en) * 2011-06-20 2014-11-05 Hetero Research Foundation PROCESS FOR BENDAMUSTINE HYDROCHLORIDE
US8987469B2 (en) 2012-07-24 2015-03-24 Heyl Chemisch-Pharmazeutische Fabrik Gmbh & Co. Kg Process for the preparation of bendamustine
MX2015005805A (es) 2012-11-12 2016-04-15 Ignyta Inc Derivados de bendamustina y métodos para utilizarlos.
US20140275567A1 (en) 2013-03-15 2014-09-18 Johnson Matthey Plc Process for preparing alkyl esters of 4-(5-(bis(2-hydroxyethyl)amino)-1-methyl-1h-benzo[d]imidazol-2-yl)butyric acid

Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE34727C (de) Ch. H. TH. HAVEMANN in Paris, 16 rue Bleue Verfahren zur direkten Gewinnung metallischen Bleis
DD159877A1 (de) 1981-06-12 1983-04-13 Wolfgang Krueger Verfahren zur herstellung von 4-[1-methyl-5-bis(2-chloraethyl)amino-benzimidazolyl-2]-buttersaeure
US20060128777A1 (en) 2004-11-05 2006-06-15 Bendall Heather H Cancer treatments
US20060159713A1 (en) 2005-01-14 2006-07-20 Cephalon, Inc. Bendamustine pharmaceutical compositions
WO2009120386A2 (en) 2008-03-26 2009-10-01 Cephalon, Inc. Novel solid forms of bendamustine hydrochloride
WO2010036702A1 (en) 2008-09-25 2010-04-01 Cephalon, Inc. Liquid formulations of bendamustine
WO2010042568A1 (en) 2008-10-08 2010-04-15 Cephalon, Inc. Processes for the preparation of bendamustine
US20100234435A1 (en) * 2007-11-08 2010-09-16 Bhattacharya Samit K Cycloalkylamino acid derivatives
WO2011079193A2 (en) 2009-12-23 2011-06-30 Dr. Reddy's Laboratories Ltd. Preparation of bendamustine and its salts
WO2012007966A2 (en) * 2010-07-15 2012-01-19 Biophore India Pharmaceuticals Pvt. Ltd. Process for preparation of intermediates of bendamustine

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DD34727A1 (de) 1963-12-21 1964-12-28 Dietrich Krebs Verfahren zur Herstellung von 1-Stellung substituierten [5-Bis-(chloräthyl)-amino-benzimidazolyl-(2)]-alkancarbonsäuren
US7378409B2 (en) * 2003-08-21 2008-05-27 Bristol-Myers Squibb Company Substituted cycloalkylamine derivatives as modulators of chemokine receptor activity
SI2367542T1 (sl) * 2008-12-03 2014-05-30 Astellas Deutschland Gmbh Oralne dozirne oblike bendamustina
CN101948436B (zh) * 2010-06-28 2012-10-03 江苏奥赛康药业股份有限公司 一种高纯度盐酸苯达莫司汀的制备方法

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE34727C (de) Ch. H. TH. HAVEMANN in Paris, 16 rue Bleue Verfahren zur direkten Gewinnung metallischen Bleis
DD159877A1 (de) 1981-06-12 1983-04-13 Wolfgang Krueger Verfahren zur herstellung von 4-[1-methyl-5-bis(2-chloraethyl)amino-benzimidazolyl-2]-buttersaeure
US20060128777A1 (en) 2004-11-05 2006-06-15 Bendall Heather H Cancer treatments
US20060159713A1 (en) 2005-01-14 2006-07-20 Cephalon, Inc. Bendamustine pharmaceutical compositions
US20100234435A1 (en) * 2007-11-08 2010-09-16 Bhattacharya Samit K Cycloalkylamino acid derivatives
WO2009120386A2 (en) 2008-03-26 2009-10-01 Cephalon, Inc. Novel solid forms of bendamustine hydrochloride
WO2010036702A1 (en) 2008-09-25 2010-04-01 Cephalon, Inc. Liquid formulations of bendamustine
WO2010042568A1 (en) 2008-10-08 2010-04-15 Cephalon, Inc. Processes for the preparation of bendamustine
WO2011079193A2 (en) 2009-12-23 2011-06-30 Dr. Reddy's Laboratories Ltd. Preparation of bendamustine and its salts
WO2012007966A2 (en) * 2010-07-15 2012-01-19 Biophore India Pharmaceuticals Pvt. Ltd. Process for preparation of intermediates of bendamustine

Non-Patent Citations (11)

* Cited by examiner, † Cited by third party
Title
Coggiola et al., Bioorganic & Medicinal Chemistry Letters, 2005, 15, pp. 3551-3554. *
Disclosed Anonymously, "Process for Preparing 4-[5-[BIS(2-Chloroethyl)Amino]-1-Methylbenzimidazol-2-YL) Butanoic Acid Intermediate," IP.com, Jul. 13, 2009, pp. 1-4.
Emmerson et al., Organic & Biomolecular Chemistry, 2003, 1(21), pp. 3826-3838. *
Gao et al., "Synthesis of Bendamustine," Chinese Journal of New Drugs, 2007, vol. 16, No. 23, 1960-1961. (English translation included.).
Ghosh et al., Tetrahedron Letters, 2010, 51, pp. 3177-3180. *
Hilal, Estimation of Hydrolysis Rate Constants of Carboxylic Acid Ester and Phosphate Ester Compounds in Aqueous Systems from Molecular Structure by SPARC, EPA/600/R-06/105, Sep. 2006. *
Leopoldo et al., Journal of Pharmacy and Pharmacology, 2006, 58, pp. 209-218. *
Ozegowski et al., "IMET 3393, gamma-[1-methyl-5-bis-(beta-chloroethyl)-aminobenzimidazolyl-(2)]-butyric acid hydrochloride, a new cytostatic drug from the benzimidazole mustard gas series," Journal of Abstracts and Reviews for Pharmacy, Pharmacotherapy, and Laboratory Diagnostics , 110 ( 1971 ), No. 10, pp. 1013-1019. (English translation included.).
Ozegowski et al., "IMET 3393, γ-[1-methyl-5-bis-(β-chloroethyl)-aminobenzimidazolyl-(2)]-butyric acid hydrochloride, a new cytostatic drug from the benzimidazole mustard gas series," Journal of Abstracts and Reviews for Pharmacy, Pharmacotherapy, and Laboratory Diagnostics , 110 ( 1971 ), No. 10, pp. 1013-1019. (English translation included.).
Ozegowski et al., "W-[bis-(chloroethyl)-amino-benzimidazolyl(2)]-propionic or -butyric acids as potential cytostatic agents," Journal für Praktische Chemie, Series 4, vol. 20, 1963 (178-186).
Rosen et al., ACS Medical Chemistry Letters, Oct. 5, 2010, 1(9), pp. 526-529. *

Also Published As

Publication number Publication date
CN104011029A (zh) 2014-08-27
US9643932B2 (en) 2017-05-09
ES2613838T3 (es) 2017-05-26
US20150105561A1 (en) 2015-04-16
EP2760842B1 (en) 2016-11-16
WO2013046223A1 (en) 2013-04-04
CN104011029B (zh) 2016-06-08
EP2760842A1 (en) 2014-08-06
US20140121383A1 (en) 2014-05-01

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